Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].CCCCCC.Cl[CH2:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1>CN(C=O)C.O>[C:25]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:6]2[CH3:12])[CH:24]=1
Reactant: ClCc1cccc(-c2ccccc2)c1
Reactant: COc1cccc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
805 mg (5 mmol) of 4-methoxy-2-methyl-1H-indole is reacted with 200 mg (5 mmol) of 60% NaH/mineral oil (washing with hexane before adding DMF) in 15 mL of DMF and after stirring for 0.5 hour, 1.0 g (5 mmol) of 3-(chloromethyl)biphenyl is added. The mixture is stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue is chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.25 g (76% yield) of 1-((1,1'-biphenyl)-3-ylmethyl)-2-methyl-4-methoxy-1H-indole mp, 127°-131° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH2:30])[CH3:26].Cl.CCN(CC)CC>C1COCC1>[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH:30][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:26]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CCCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
4-Phenylbutyric acid (2.46 g, 15 mmol) was dissolved in distilled THF (70 ml) in an argon atmosphere. After cooling in an ice bath, carbonyldiimidazole (CDI) (2.43 g, 1.5 mmol) was added and the mixture was stirred cold 1 hour and at room temperature 1 hour. The mixture was then cooled and glycine ethyl ester.HCl (2.09 g, 15 mmol) and distilled Et3N (2.1 ml, 15 mmol) were added. The mixture was left stirring overnight at room temperature. After removal of the solvent in vacuo, Et2O (200 ml) was added. The solution was washed with 1N HCl (70 ml), 0.5N NaOH (70 ml) and saturated NaCl solution (70 ml), dried (MgSO4) and freed of solvent in vacuo leaving title compound (3.13 g, 84%) as white crystalline material. TLC: silica gel, Et2O, UV; Rf : 0.58.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:32][S:33]([C:36]1[S:40][C:39]([NH2:41])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH2:30][OH:31])[CH3:29]>>[OH:31][CH2:30][C:28]([NH:32][S:33]([C:36]1[S:40][C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH2:27][OH:26])[CH3:29]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(CO)CO
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(CO)CO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.9) according to general procedure II. Yellow solid. MS (ISP) 619.2 [(M−H)−]; mp 248° C.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:14]([CH2:15][C@@H:16]([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.[C:33]([O:36][C@H:37]1[CH2:42][CH2:41][C@H:40]2[C@H:43]3[C@H:57]([CH2:58][CH2:59][C@:38]12[CH3:39])[C@:51]1([CH2:52][O:53]C(=O)C)[C:46]([CH2:47][C@@H:48]([O:60][C:61]2([O:66][CH3:67])[CH2:65][CH2:64][CH2:63][CH2:62]2)[CH2:49][CH2:50]1)=[CH:45][CH2:44]3)(=[O:35])[CH3:34].C(O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(COC(=O)C)C(C[C@@H](OCC)CC1)=CC3)(=O)C>>[C:22]([O:21][CH2:20][C@@:19]12[C@@H:25]3[C@H:11]([C@H:8]4[C@@:6]([CH2:27][CH2:26]3)([CH3:7])[C@@H:5]([OH:4])[CH2:10][CH2:9]4)[CH2:12][CH:13]=[C:14]1[CH2:15][C@@H:16]([O:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[CH2:17][CH2:18]2)(=[O:24])[CH3:23].[C:33]([O:36][C@H:37]1[CH2:42][CH2:41][C@H:40]2[C@H:43]3[C@H:57]([CH2:58][CH2:59][C@:38]12[CH3:39])[C@:51]1([CH2:52][OH:53])[C:46]([CH2:47][C@@H:48]([O:60][C:61]2([O:66][CH3:67])[CH2:65][CH2:64][CH2:63][CH2:62]2)[CH2:49][CH2:50]1)=[CH:45][CH2:44]3)(=[O:35])[CH3:34]
Reactant: CC(=O)OC[C@]12CC[C@H](O[Si](C)(C)C)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reactant: COC1(O[C@H]2CC[C@@]3(COC(C)=O)C(=CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](OC(C)=O)CC[C@@H]43)C2)CCCC1
Agent: CCO[C@H]1CC[C@@]2(COC(C)=O)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Product: CC(=O)OC[C@]12CC[C@H](O[Si](C)(C)C)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Product: COC1(O[C@H]2CC[C@@]3(CO)C(=CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](OC(C)=O)CC[C@@H]43)C2)CCCC1

Procedure:
Substituting 3β-trimethylsiloxy-5-androstene-17β,19-diol diacetate, 3β-(1'-methoxycyclopentyloxy)-5-androstene-17β,19-diol diacetate and 3β-(1'-cyclopentenyloxy)-5-androstene-17β,19-diol diacetate for the 3β-ethoxy-5-androstene-17β,19-diol diacetate above results in the preparation of 3β-trimethylsiloxy-5-androstene-17β,19-diol 19-acetate, 3β-(1'-methoxycyclopentyloxy)-5-androstene-17β,19-diol 17-acetate and 3β-(1'-cyclopentenyloxy)-5-androstene-17β,19-diol 17-acetate, respectively.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:10])[CH2:8]Br)=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:16]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]=1>CCOCC.CC(C)=O>[BrH:1].[NH2:11][CH:12]1[N:16]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[N:13]1[CH2:8][C:7](=[O:10])[C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Nc1nc2ccccc2n1CCN1CCCCC1
Reactant: O=C(CBr)c1ccc(Br)s1
Solvent: CC(C)=O
Solvent: CCOCC
Product: Br
Product: NC1N(CCN2CCCCC2)c2ccccc2N1CC(=O)c1ccc(Br)s1
Temperature: 25 °C
Yield: 82 %

Procedure:
Add a solution of 5-bromo-2-bromoacetylthiophene (5.68 g, 20 mmol) in 30 ml of ether to a hot solution of 2-amino-1-(2-piperidinoethyl)-benzimidazole (4.88 g, 20 mmol) in 150 ml of acetone. Stir and maintain at room temperature for five hours. Suction-filter the precipitate, wash with acetone and then with ether to obtain the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>C(Cl)Cl>[CH3:1][C@H:2]1[N:7]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
To a solution of 1,1-dimethylethyl(3R)-3-methyl-1-piperazinecarboxylate (605 mg, 2.56 mmol) in DCM (20 ml) was added DIPEA (1.12 ml, 6.39 mmol) and then portionwise 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (0.455 ml, 2.68 mmol) at room temp and the resultant mixture stirred under Ar for 16 h. DCM (75 ml) and a 1M HCl solution (75 ml) were added, the layers were separated and the organic layer was then washed with 2M NaOH solution (75 ml), the organic layers were separated, dried (MgSO4) and concentrated to dryness. 1,1-Dimethylethyl(3R)-3-methyl-4-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-1-piperazinecarboxylate was isolated as a slowly crystallizing white solid.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2N)CC1
Yield: 99.3 %

Procedure:
To a solution of 4,6-dichloro-5-aminopyrimidine (1 g, 6.1 mmol) in TEA (2 mL) and toluene (10 mL) was added 1-Boc-piperazine (2.3 g, 12.3 mmol). The mixture was refluxed for 12 hours. The solvent was removed and the residue was subject to chromatography on silica gel to afford the product 4-(5-amino-6-chloropyrimidin-4-yl)-piperazin-1-carboxylic acid tert-butyl ester (1.9 g, 99%). 1H NMR (CDCl3, 400 Hz) δ 8.16 (s, 1H), 3.87 (s, 2H), 3.56 (m, 4H), 3.29 (m, 4H), 1.49 (s, 9H). MS (ESI+) [M+H]+ 314.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.NC1C(C)=C(C)C=CN=1.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][N:19]=1>>[C:5]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([CH3:25])=[CH:20][N:19]=1)(=[O:7])[CH3:6]
Reactant: Cc1cnc(N)cc1C
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccnc(N)c1C
Product: CC(=O)Nc1cc(C)c(C)cn1
Temperature: 137.5 °C

Procedure:
Acetic anhydride (2.0 mL, 21 mmol) and 500 mg (4.09 mmol) of a 4:1 mixture of 2-amino-3,4-dimethylpyridine and 2-amino-4,5-dimethylpyridine (prepared by the method of W. O. Siegl, J. Heterocycl. Chem. 1981, 18, 1613-1618) were heated in a 135-140° C. oil bath for 2 h. The solution was concentrated on a rotary evaporator and the residue was chromatographed twice on silica gel, eluted with 30-50% ethyl acetate in dichloromethane to give 71 mg of pure 2-acetamido-4,5-dimethylpyridine.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)=[O:7])(C)(C)C.[CH2:18](N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.C(OCC)(=O)C>[C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:10]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:12])(=[O:7])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)O
Reactant: CCN(CC)CC
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-(difluoromethoxy)propanoic acid (197 mg, 1.0 mmol) and triethylamine (303 mg, 3 mmol) in THF (10 mL) at −78° C., isobutyl chloroformate (174 mg, 1.28 mmol) was added dropwise. After 30 minutes, benzylamine (161 mg, 1.5 mmol) was added and the reaction mixture was allowed to warm up to room temperature. The mixture then was diluted with ethyl acetate and washed with water, 0.5N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated, and triturated with ether-hexanes (1:3) to give (2R)-2-(acetylamino)-N-benzyl-3-(difluoromethoxy)propanamide (48 mg, 16.7%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.25-7.39 (m, 5H), 6.68 (w, 1H), 6.42 (d, 1H), 6.24 (wt, 1H), 4.73 (m, 1H), 4.48 (d, 2H), 4.24 (dd, 1H), 4.01 (dd, 1H) and 2.05 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12](Cl)[CH:13]=[CH2:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:14]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH:13]=[CH2:12]
Reactant: C=CCCl
Agent: Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCNc1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
Toluene (1,830 g) and m-trifluoromethylaniline (1,127 g; 7 moles) were introduced in an inert atmosphere into a 6 liter round flask. The reaction medium was stirred and heated to a temperature of 110° C. At that temperature, allyl chloride (382.5 g; 5 moles) and triethylamine (506 g; 5 moles) were added in parallel, over approximately 3 hours, with a lead of the order of 10% for allyl chloride. When the addition was complete, the reaction medium was maintained at a temperature of 115° C. for 1 hour and was then cooled to a temperature 30° C. The reaction mass was washed with water (4 washes with a total of 1.3 liter of water), to extract triethylamine hydrochloride. The organic phase was then distilled at atmospheric pressure and then under reduced pressure (<3,000 Pa). This resulted in the separation of toluene and unconverted m-trifluoromethylaniline (460 g; 2.86 moles) from N-allyl-m-trifluoromethylaniline (588 g; 2.92 moles), which corresponds to a 57% yield based on allyl chloride and 70% based on converted m-trifluoromethylaniline.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[NH3:24]>CO>[F:22][C:18]1[CH:17]=[C:16]([CH:15]=[CH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:24])=[O:2])=[CH:9][CH:10]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CC(=O)Nc1ccc(C=Cc2cccc(F)c2)cc1
Reactant: N
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(C=Cc2cccc(F)c2)cc1
Yield: 68 %

Procedure:
Prepared in analogy to example 3 from N-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield=68%. Colorless solid. MS: m/e=299.2 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](O)[CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>C(Cl)Cl.O>[N:23]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)[CH3:9])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1ccc(F)cn1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(5-Fluoropyridin-2-yl)ethanol (Method 2; 7.5 g, 53.1 mmol) and triethyl amine (9.3 ml, 66.4 mmol) in anhydrous DCM (50 ml) was added methanesulfonyl chloride (4.5 ml, 58.5 mmol) at 0° C. After adding, the reaction was warmed to room temperature and stirred at room temperature for 2 hours. The solvent was removed. The residue was dissolved in anhydrous DMF (50 ml) and sodium azide (6.9 g, 106 mmol) was added. The reaction stirred at room temperature for 2 hours. Water (50 ml) was added and extracted with ether (2×75 ml).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:15])[C:12](=[O:14])[CH3:13]>[OH-].[Na+].C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12](=[O:14])[CH:11]([CH3:15])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
4-Bromo-benzaldehyde (available from Aldrich, 10.0 g, 54.3 mmol) was added to a solution of 3-methyl-butan-2-one (available from Aldrich, 4.7 g, 54.7 mmol) in 10 mL of 10% NaOH(aq) and 20 mL of ethanol. After stirring at room temperature for 3 h, the reaction mixture was diluted with water (50 mL) and extracted with diethyl ether (3×20 mL). The organic layer was then washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (95:5 hexane/ethyl acetate) yielded the title compound (7.98 g, 58% yield) as a light yellow oil:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:14][CH:13]=2)[CH:11]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1.C1(C)C=CC=CC=1.C1C=CC=CC=1>CCOCC>[F:1][C:2]([F:36])([F:35])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:14][CH:13]=2)[CH:11]=1)=[S:46]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NCC(F)(F)F)nc3-c3ccccc3Cl)cc2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=S)NCC(F)(F)F)nc3-c3ccccc3Cl)cc2)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a 25 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 2-(2-Chloro-phenyl)-1-(3′-methanesulfonyl-biphenyl-4-yl)-1H-imidazole-4-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (65 mg, 127 μmol), Lawesson's Reagent (230 mg, 570 μmol), and anhydrous toluene (6 mL). The reaction solution was allowed to stir at reflux 5 hrs prior to TLC analysis showing full transformation of starting material. The reaction solution was allowed to cool to room temperature prior to addition of a 1:1 mixture of benzene and Et2O. The resulting precipitate was removed by vacuum filtration through a Buchner funnel. The filtrate was concentrated on the Rotavapor and the crude residue was chromatographed through a 12 g SiO2 column using a mobile phase gradient of 100% Hx to 50% EtOAc to afford 55 mg (79% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ 9.21 (t, 1H), 8.11 (s, 1H), 8.04 (t, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.59 (t, 1H), 7.53-7.46 (m, 4H), 7.34-7.311 (m, 3H), 7.18 (d, 2H), 4.56 (m, 2H), 3.02 (s, 3H); 19F NMR (400 MHz, CDCl3) δ −70.8 ppm; MS (ES): 550.3, 552.3 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.Cl.[NH2:35][N:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38].[F:48][C:49]([F:76])([F:75])[C:50]1[CH:58]=[C:57](/[CH:59]=[CH:60]/[CH:61]([C:66]2[CH:71]=[C:70]([Cl:72])[C:69]([Cl:73])=[C:68]([Cl:74])[CH:67]=2)[C:62]([F:65])([F:64])[F:63])[CH:56]=[CH:55][C:51]=1[C:52](O)=[O:53]>CN(C=O)C.O>[CH:45]([N:36]([C:37]([NH:39][CH2:40][C:41]([F:43])([F:42])[F:44])=[O:38])[NH:35][C:52](=[O:53])[C:51]1[CH:55]=[CH:56][C:57](/[CH:59]=[CH:60]/[CH:61]([C:66]2[CH:67]=[C:68]([Cl:74])[C:69]([Cl:73])=[C:70]([Cl:72])[CH:71]=2)[C:62]([F:63])([F:64])[F:65])=[CH:58][C:50]=1[C:49]([F:75])([F:76])[F:48])([CH3:47])[CH3:46]
Reactant: CC(C)N(N)C(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F)C(=O)NCC(F)(F)F
Reaction time: 4 h
Yield: 32.5 %

Procedure:
DIPEA (0.32 ml, 1.88 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (263 mg, 0.69 mmol) and 1-amino-1-isopropyl-3-(2,2,2-trifluoroethyl)urea hydrochloride (178 mg, 0.75 mmol) were added to a stirred solution of 2-(trifluoromethyl)-4-[(E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl]benzoic acid (300 mg, 0.63 mmol) in DMF (2 mL) at ambient temperature and the reaction mixture was stirred for 4 h. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica, eluting with 20% EtOAc in petroleum ether to afford the title compound as a brown gum (135 mg, 29%).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14](=[O:22])[NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cnccn1)[C@@H]1C[C@@H](F)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,4R)-tert-butyl 4-fluoro-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 65A (4.1 g, 12.3 mmol) in CH2Cl2 (120 mL) was added TFA (10 mL). The reaction mixture was stirred at rt overnight. After concentration in vacuo, the residue was used for the next step without purification. LC/MS [M+H]+: 211; Ret time (Method F): 0.30 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([Se]C3C=CC=CC=3)[C:6]=2[N:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]=[CH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2c1CCCC2[Se]c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Clc1ccnc2c1CCC=C2
Yield: 93.8 %

Procedure:
This compound was prepared from the product of Step 3 (9 g, 28 mmol), 86% 3-chloroperoxybenzoic acid (5.8 g, 29 mmol), and dichloromethane (150 ml) using the procedure outlined in Example 25. Step 2. Distillation gave the product (4.35 g) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.[CH3:11][Si](C[Mg]Cl)(C)C.C(OCC)C>C1COCC1>[CH2:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][CH:9]=[CH2:11]
Reactant: O=CCCc1cccnc1
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCc1cccnc1
Reaction time: 0.25 h

Procedure:
3-(Pyridin-3-yl)propanal (10 g, 74 mmol) is dissolved in THF (200 ml), and thereto is added a solution of trimethylsilylmethyl magnesium chloride in diethyl ether (100 ml, 100 mmol) under ice-cooling, and the mixture is stirred for 15 minutes. The reaction is quenched with a saturated brine (10 ml), and the mixture is extracted with ethyl acetate (300 ml×2), washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added THF (50 ml) and conc. sulfuric acid (5 ml), and the mixture is heated under reflux for 20 minutes. After being allowed to cool, the reaction solution is neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (200 ml×2). The organic layer is washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-(3-butenyl)pyridine (6.5 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH2:15])[CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].C(N(CC)CC)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>ClCCl>[CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([NH:15][S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:32])=[O:31])[CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@H](CNC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
The compound obtained in the above (3) is dissolved in dichloromethane (15 ml), and thereto are added triethylamine (2.0 ml) and benzenesulfonyl chloride (1.57 ml) at room temperature, and the mixture is stirred for 30 minutes. To the mixture are further added triethylamine (0.57 ml) and benzenesulfonyl chloride (0.52 ml), and the mixture is further stirred for 30 minutes. The reaction mixture is poured into water, and the mixture is extracted three times with ethyl acetate. The extract is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, solvent; hexane/ethyl acetate=1:1). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (2.69 g) as a colorless powder.